Sex-Specific Effects of Nutritional Supplements for Infants Born Early or Small: An Individual Participant Data Meta-Analysis (ESSENCE IPD-MA) II: Growth

Luling Lin, Greg D. Gamble, Caroline A. Crowther, Frank H. Bloomfield, Massimo Agosti, Stephanie A. Atkinson, Augusto Biasini, Nicholas D. Embleton, Fernando Lamy Filho, Christoph Fusch, Maria L. Gianni, Hayriye Gözde Kanmaz Kutman, Winston Koo, Ita Litmanovitz, Colin Morgan, Kanya Mukhopadhyay, Erica Neri, Jean Charles Picaud, Niels Rochow, Paola RoggeroKenneth Stroemmen, Maw J. Tan, Francesco M. Tandoi, Claire L. Wood, Gitte Zachariassen, Jane E. Harding*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review


Neonatal nutritional supplements may improve early growth for infants born small, but effects on long-term growth are unclear and may differ by sex. We assessed the effects of early macronutrient supplements on later growth. We searched databases and clinical trials reg-isters from inception to April 2019. Participant-level data from randomised trials were included if the intention was to increase macronutrient intake to improve growth or development of infants born preterm or small-for-gestational-age. Co-primary outcomes were cognitive impairment and metabolic risk. Supplementation did not alter BMI in childhood (kg/m2: adjusted mean difference (aMD) −0.11[95% CI—0.47, 0.25], p = 0.54; 3 trials, n = 333). Supplementation increased length (cm: aMD 0.37[0.01, 0.72], p = 0.04; 18 trials, n = 2008) and bone mineral content (g: aMD 10.22[0.52, 19.92], p = 0.04; 6 trials, n = 313) in infancy, but not at older ages. There were no differences between supplemented and unsupplemented groups for other outcomes. In subgroup analysis, supplementation increased the height z-score in male toddlers (aMD 0.20[0.02, 0.37], p = 0.03; 10 trials, n = 595) but not in females, and no significant sex interaction was observed (p = 0.21). Macronutrient supplementation for infants born small may not alter BMI in childhood. Supplemen-tation increased growth in infancy, but these effects did not persist in later life. The effects did not differ between boys and girls.

Original languageEnglish
Article number392
Issue number2
StatePublished - 1 Jan 2022
Externally publishedYes


  • Growth
  • Individual participants data meta-analysis
  • Macronutrient supplementation
  • Preterm infants
  • Small-for-gestational-age infants
  • Systematic review


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